A. Effects of Implantable Devices
Implantable medical devices made of various materials may cause a number of iatrogenic effects in patients. First, implantable medical devices can serve as foci for infection of the body. Infection is promoted by the tendency of bacterial organisms to adhere to the surfaces of implantable devices and, while adherent, to resist destruction by phagocytic cells that normally would destroy these organisms.
Second, implantable devices also tend to serve as a nidus, or focus, for the formation of thrombi (blood clots). This is because the surfaces of the implanted materials may activate non-cellular plasma clotting factors. Furthermore, platelets which adhere to the surfaces of these materials become activated and form thrombi. The procoagulant activities of many materials can prevent their use in vivo, or can greatly diminish their useful lifetime. In addition, even materials which are chemically inert may act as foci for the formation of inflammatory lesions such as granulomas, resulting, in many cases, in the necessity for removal of the implanted device.
B. Calcification of Animal Tissue Implants
Aldehydes such as formaldehyde and especially glutaraldehyde are commonly used to control the physical and biological properties of a variety of animal tissue derived materials such as tissue heart valves and other tissue-derived implantable devices. It is well established that pre-treatment of protein-containing biological tissue material with aldehydes causes a cross-linking reaction with the amine groups in the protein which reduces the solubility, antigenicity, and biogradation of the treated material. However, it is also well-known that such implants must be treated to avoid problems after implantation, for example, excessive mineralization or calcification and rejection by the body's immune system.
Numerous treatments for preventing calcification and improving the stability of prosthetic devices made from natural tissue have therefore been proposed.
In U.S. Pat. No. 5,002,566 issued to Carpentier et al., a calcification resistant bioprosthetic implant is described which is made from tanned biological material which has been impregnated with a calcification-mitigating amount of a ferric and/or stannic salt.
In U.S. Pat. No. 4,976,733 issued to Girardot, a method for retarding or preventing the calcification of a prosthesis implanted in a mammal is described in which before implantation an effective amount of an anticalcification agent is coupled to the prosthesis in the form of an aliphatic carboxylic acid. For a natural tissue prosthesis, such coupling may be to an aldehyde group of glutaraldehyde in which the tissue is pre-soaked.
In U.S. Pat. No. 4,885,005 issued to Hashef et al., a process for the preparation of implantable biological tissue is described, and in particular bioprosthetic heart valves, which are prone to calcification after implantation in which the process includes the treatment of tissue with an effective amount of a surfactant to reduce calcification of the implanted tissue.
In U.S. Pat. No. 4,838,888 issued to Nashef, a process for treating biological tissue prior to implantation to mitigate the calcification of the tissue following implantation is described, incorporating acetylsalicylic acid into the tissue in an amount effective to reduce calcification of the tissue after it is implanted.
In U.S. Pat. No. 4,770,665 issued to Nashef, a process for the preparation of implantable biological tissue is described wherein elastomeric copolymers are incorporated into the tissue in an amount sufficient to increase the durability of the tissue as well as to reduce calcification of the tissue upon implantation.
In U.S. Pat. No. 4,753,652 issued to Langer et al., a biomaterial implant is described into which is incorporated a sustained release polymer containing an anticalcium agent (e.g., ethanehydroxydiphosphonate (EHDP), EDTA, or aminopropanediphosphonate (APDP).
In U.S. Pat. No. 4,729,139 issued to Nashef, a process for selectively incorporating biocompatible polymers in the interstices of implantable biological tissue is described in which the outer surface of the tissue is left substantially free of bonded polymer. The process involves covalently binding a monomer to the tissue, contacting the tissue with a free-radical initiator, then contacting the tissue with a solution containing a second monomer and a free-radical scavenger, thereby promoting selective polymerization of the second monomer with the portion of covalently-bound first monomer which is located in the interstices of the tissue.
In U.S. Pat. No. 4,648,881 and 4,647,283 issued to Carpentier et al., a process for the preparation of implantable biological tissue is described which has been found effective in reducing calcification of the implanted tissue in which the tissue is contacted with a phosphate-deficient solution or a calcium-binding competing divalent cation.
In U.S. Pat. No. 4,553,974 issued to Dewangee, a process for treatment of collagenous tissue used in a prosthetic implant (e.g., a heart valve) is described in which a surfactant, an anti-calcification agent (i.e., amino diphosphonates) and, optionally, a stabilizing agent are used to prevent calcification.
In U.S. Pat. No. 4,481,009 issued to Nashef, a process is disclosed for the preparation of implantable biological tissue which includes the incorporation of biocompatible polymers into the tissue in an amount effective in reducing calcification of the implanted tissue (e.g., the covalent immobilization of monomers onto the biological tissue followed by further polymerization).
In U.S. Pat. No. 4,405,327 issued to Pollock, natural tissues are fixed with a tanning solution such as glutaraldehyde and treated with a solution of a water soluble quaternary ammonium salt such as dodecyltrimethylammonium chloride to inhibit calcification of the tissue after implantation.
In U.S. Pat. No. 4,402,697 issued to Pollock et al., natural tissues fixed with a tanning solution such glutaraldehyde are treated with a solution of a water soluble phosphate ester such as sodium dodecyl hydrogen phosphate to inhibit calcification of the tissue after implantation.
In U.S. Pat. No. 4,378,224 issued to Nimni et al., a coating and integral treating for improving the calcification of heart valves is described with covalently attached calcification inhibitors (e.g., natural protein polysaccharides, such as chondroitin sulfates and hyaluronate; diphosphonates, phosphoproteins, dyes, such as alzarin red S and methylene blue, and other polyanions may be used).
In U.S. Pat. No. 4,323,358 issued to Lentz et al., treatment of a glutaraldehyde-fixed animal tissue with a solution of a water-soluble salt of a sulfated higher aliphatic alcohol is disclosed, such as sodium dodecyl sulfate, to inhibit calcification of the tissue after implantation.
However, there is still a need for methods to render the surfaces of implantable tissue-derived materials less thrombogenic, less pro-inflammatory and less prone to calcification.
C. Albumin Selectivity
Albumin is the predominant plasma protein, readily soluble in water and in constant contact with the luminal surface of the vascular endothelium. The vascular endothelium itself imparts several desirable characteristics to the walls of blood vessels, including diminished tendency to promote coagulation, reduced attractiveness for inflammatory, phagocytic cells, and increased ability to resist colonization by pathogenic bacteria.
In its normal configuration, albumin does not promote clotting nor attract inflammatory cells. It has been found to be desirable to coat the surfaces of medical devices with albumin, thereby imparting these same characteristics to the surface of biomaterial. In U.S. Pat. No. 5,073,171 issued to Eaton, a biocompatible prosthetic device is described in which a synthetic material from which it is made incorporates an amount of an albumin-binding dye effective to form a coating of endogenous albumin on the device when the device is in contact with a physiological fluid containing albumin.